The current proposal outlines a research training program in which I will pursue sophisticated studies of the earliest lesions in pancreatic cancer (PanIN) initiation and progression under the mentorship of Dr. Steven Leach at Johns Hopkins University. Greater than 80% of pancreatic cancer patients have Kras mutations and the exact cell of origin for pancreatic cancer has not been defined. Therefore, we propose to develop a "next generation" mouse model of PanIN formation, in which we label cells with green flourescent protein (GFP) fused to Kras to image cells in the pancreas that have undergone recombination and express activated Kras. We will activate Kras in the acinar or ductal compartment of adult mouse pancreas. With the GFP:Kras fusion, we will be able to identify, visualize and isolate cells at discreet time points following activation of oncogenic Kras expression, empowering a series of novel experiments in which the cellular response to pancreatic Kras activation can be studied even prior to the formation of PanIN lesions, and with unprecedented spatial and temporal resolution. Using this novel approach, we will test the following hypotheses: First, that even prior to the onset of morphologic PanIN formation, individual pancreatic epithelial cells respond to oncogenic Kras expression with progressive changes in gene expression, proliferation, and morphology;second, that acinar and ductal cells may exhibit differences in these responses;third, that chronic pancreatitis influences the response to Kras, and finally, that understanding these earliest responses will allow the pharmacologic termination of PanIN initiation and progression. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is an incredibly lethal form of cancer with a less than 5% chance of two year survival after diagnosis. We are proposing to study the earliest initiating events of pancreatic cancer to identify novel pathways for the treatment or diagnosis of this lethal disease. We believe these studies are relevant to better understand the earliest responses of ductal or acinar cells to oncogenic Kras activation.